Amanda Nicoll

Iron-overload-related disease in HFE hereditary hemochromatosis.

BACKGROUND Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial. METHODS We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. RESULTS The proportion of C282Y homozygotes with documented iron-overload-related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload-related disease. Male C282Y homozygotes with a serum ferritin level of 1000 mug per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene. CONCLUSIONS In persons who are homozygous for the C282Y mutation, iron-overload-related disease developed in a substantial proportion of men but in a small proportion of women.

Tenofovir disoproxil fumarate rescue therapy following failure of both lamivudine and adefovir dipivoxil in chronic hepatitis B

Objective To determine the efficacy of tenofovir disoproxil fumarate (TDF) in adults with chronic hepatitis B virus (HBV) infection who had previously failed lamivudine (LAM) and had significant viral replication (HBV DNA >105 copies/ml if HBeAg positive, >104 copies/ml if HBeAg negative) despite at least 24 weeks of treatment with adefovir dipivoxil (ADV). Design A prospective open-label study of TDF 300 mg daily. Patients receiving combination ADV/LAM prior to baseline were switched to TDF/LAM. Setting Multiple tertiary referral centres. Methods Sixty patients were enrolled. The median age was 48.5 years (range 21–80), 46 (77%) were male and 40 (67%) were HBeAg positive. Thirty-eight patients (63%) were switched from ADV to TDF, the remainder from ADV/LAM to TDF/LAM. At baseline, substitutions conferring resistance to LAM or ADV were present in 20 patients (33%) and 17 patients (28%), respectively. The median baseline viral load was 5.33 log10 IU/ml (range 2.81–8.04). Patients initially treated with TDF monotherapy with persistent viral replication at or after 24 weeks were switched to TDF/LAM. The main outcome measures were change in HBV viral load from baseline and percentage of patients achieving an undetectable viral load (<15 IU/ml). Results Results are reported at 96 weeks of treatment. One patient discontinued TDF at 10 days due to rash. The time-weighted change in viral load from baseline to week 12 was −2.19 log10 IU/ml overall. The median change in HBV DNA from baseline to weeks 12, 24, 48 and 96 was −2.86, −3.23, −3.75 and −4.03 log10 IU/ml, respectively. At 48 and 96 weeks, 27/59 (46%) and 38/59 (64%) patients achieved a HBV DNA <15 IU/ml. The response was independent of baseline LAM therapy or mutations conferring ADV resistance. Conclusions In heavily pretreated patients with a high rate of genotypic resistance, TDF retains significant activity against HBV although this appears diminished in comparison with studies of naïve patients.

Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis

HFE-associated hereditary haemochromatosis is a recessive, iron-overload disorder that affects about one in 200 north Europeans and that can be easily prevented. However, genetic screening for this disease is controversial, and so we assessed whether such screening was suitable for communities. Cheek-brush screening for the Cys282Tyr HFE mutation was offered to individuals in the workplace. Outcomes were assessed by questionnaires before and after testing. 11,307 individuals were screened. We recorded no increase in anxiety in individuals who were homozygous for the Cys282Tyr mutation or non-homozygous. Self-reported tiredness before testing was significantly higher in homozygous participants than in non-homozygous participants (chi2 test, p=0.029). Of the 47 homozygous individuals identified, 46 have taken steps to treat or prevent iron accumulation. Population genetic screening for HFE-associated hereditary haemochromatosis can be practicable and acceptable.

HFE C282Y/H63D Compound Heterozygotes Are at Low Risk of Hemochromatosis-RElated Morbidity

The risk of hemochromatosis‐related morbidity is unknown among HFE compound heterozygotes (C282Y/H63D). We used a prospective population‐based cohort study to estimate the prevalence of elevated iron indices and hemochromatosis‐related morbidity for compound heterozygotes. In all, 31,192 subjects of northern European descent were genotyped for HFE C282Y and H63D. An HFE‐genotype stratified random sample of 1,438 subjects, followed for an average of 12 years to a mean age of 65 years, completed questionnaires and gave blood. Clinical examinations were blinded to HFE genotype. A total of 180 (84 males) clinically examined C282Y/H63D participants were compared with 330 (149 males) controls with neither HFE mutation; 132 (65 males) and 270 (122 males), respectively, had serum iron measures at both timepoints. Mean serum ferritin (SF) and transferrin saturation (TS) were significantly greater for male and female compound heterozygotes than for wild‐types at baseline and follow‐up (all P < 0.02) except for females who were premenopausal at baseline, where SF was similar in both genotype groups. For subjects with serum measures from both baseline and follow‐up, mean SF and TS levels did not change significantly for men or for postmenopausal women, but for premenopausal women SF levels increased from 43 to 109 μg/L for compound heterozygotes and from 35 to 64 μg/L for wild‐types (both P < 0.001). Male and female compound heterozygotes had a similar prevalence of hemochromatosis‐related morbidity to wild‐types. One of 82 males and zero of 95 females had documented iron overload‐related disease. Conclusion: For male compound heterozygotes, mean iron indices do not change during middle age but for female compound heterozygotes menopause results in increased mean SF. Although compound heterozygotes might maintain elevated iron indices during middle age, documented iron overload‐related disease is rare. (HEPATOLOGY 2009;50:94–101.)

Biliary epithelial trefoil peptide expression is increased in biliary diseases

Biliary epithelial trefoil peptide expression is increased in biliary diseases

Oral vitamin D replacement is effective in chronic liver disease

BACKGROUND & AIMS End-stage chronic liver disease is associated with vitamin D deficiency but the prevalence across a broad-spectrum of liver disease is unknown. This study prospectively examines prevalence of vitamin D deficiency and response to replacement in chronic liver disease. METHODS One hundred and fifty-eight outpatients with chronic liver disease were enrolled. Serum 25-hydroxyvitamin D (25[OH]D) levels were classified as: severely deficient less than 25 nmol/l, deficient 25-54 nmol/l or replete greater than 54 nmol/l. Sixty-five of 158 (41%) had cirrhosis. RESULTS 25[OH]D was suboptimal in 101/158 (64%), including severe deficiency in 24 patients (15%). Vitamin D deficiency occurred in liver disease of all aetiologies, including patients with only mild liver disease. 25[OH]D increased by 60.0% (19.11 ± 13.20 nmol/l) in patients with deficiency after vitamin D replacement and decreased by 25.2% (-18.33 ± 12.02 nmol/l) in non-treated initially replete patients over a median of 4 months. CONCLUSIONS Vitamin D deficiency improves with oral vitamin D supplementation and levels fall without supplementation. Chronic liver disease patients are at very high risk of vitamin D deficiency regardless of etiology or severity.

REVIEW: Present and future directions in the treatment of chronic hepatitis B infection

The last decade has witnessed substantial progress in the development of chemotherapeutic agents for chronic hepatitis B. However, the only currently licensed treatment in Australia, interferonalpha, has low initial response rates and the adverse effects are often unacceptable. Of the newer agents in the class of nucleoside analogues, famciclovir and lamivudine are in phase III clinical trials with encouraging preliminary results, while other agents, such as bis‐POM PMEA (Adefovir), are at phase I/II development. Future approaches to therapy will be governed by an understanding of the effects of nucleoside analogues on the natural history of the disease as well as on the hepatitis B virus‐hepatocyte interaction. Combination antiviral therapy should theoretically offer improved response rates, decrease the development of viral resistance, and provide the greatest reduction in viral load, but it has not yet been widely examined in the clinical setting. In this article, we review the currently available strategies, discuss potential problem areas, and speculate on promising approaches with combination chemotherapy and the features of agents soon to be trialed.

Surgical risk in patients with cirrhosis.

Surgery in the patient with cirrhosis is problematic, as encephalopathy, ascites, sepsis and bleeding are common in the postoperative period. Accurate preoperative assessment and planning, and careful postoperative management have the potential to reduce the frequency and severity of such complications, and reduce the length of hospital stay, but there is little literature evidence to prove this. Operative mortality and other risks correlate with the severity of the liver disease, co‐morbidities and the type of surgery. The Child‐Turcott‐Pugh (CTP) score or model for end‐stage liver disease (MELD) score may be used to determine the severity of the liver disease, but must also take into account recent changes in the patients condition. Surgery that does not involve opening the peritoneum may have slightly better outcomes, as the risk of ascitic leak, sepsis and difficult fluid management are reduced. Mortality rates range from 10% in CTP‐A patients to 82% in CTP‐C patients. The presence of portal hypertension is an important negative predictor, especially in abdominal surgery, as refractory ascites may occur. Careful monitoring in the postoperative period and early intervention of complications are essential. Hepatic resections in cirrhosis are associated with other considerations such as leaving sufficient liver tissue to prevent liver failure, and are beyond the scope of this review.

Analgesia for the cirrhotic patient: A literature review and recommendations

The choice of analgesic agent in cirrhotic patients is problematic and must be individualized taking into account several factors including severity of liver disease, history of opioid dependence, and potential drug interactions. With a cautious approach including slow dose up‐titration and careful monitoring, effective analgesia can be achieved in most cirrhotic patients without significant side effects or decompensation of their liver disease. Paracetamol is safe in patients with chronic liver disease but reduced doses of 2–3 grams daily is recommended for long‐term use. Non‐steroidal anti‐inflammatory drugs are best avoided because of risk of renal impairment, hepatorenal syndrome, and gastrointestinal hemorrhage. Opioids have an increased risk of toxicity particularly in patients with hypoalbuminaemia, and immediate‐release as opposed to controlled‐release formulations are advised. Co‐prescription of laxatives is mandatory to avoid constipation and encephalopathy. Adjuvant analgesics such as tricyclic antidepressants and anti‐convulsants may be used cautiously for cirrhotic patients with neuropathic pain. Gabapentin or pregabalin may be better tolerated in cirrhosis because of non‐hepatic metabolism and a lack of anti‐cholinergic side effects.

Novel population-based study finding higher than reported hepatocellular carcinoma incidence suggests an updated approach is needed

Hepatocellular carcinoma (HCC) incidence is rising rapidly in many developed countries. Primary epidemiological data have invariably been derived from cancer registries that are heterogeneous in data quality and registration methodology; many registries have not adopted current clinical diagnostic criteria for HCC and still rely on histology for classification. We performed the first population‐based study in Australia using current diagnostic criteria, hypothesizing that HCC incidence may be higher than reported. Incident cases of HCC (defined by American Association for the Study of Liver Diseases diagnostic criteria or histology) were prospectively identified over a 12‐month period (2012‐2013) from the population of Melbourne, Australia. Cases were captured from multiple sources: admissions to any of Melbournes seven tertiary hospitals; attendances at outpatients; and radiology, pathology, and pharmacy services. Our cohort was compared to the Victorian Cancer Registry (VCR) cohort (mandatory notified cases) for the same population and period, and incidence rates were compared for both cohorts. There were 272 incident cases (79% male; median age: 65 years) identified. Cirrhosis was present in 83% of patients, with hepatitis C virus infection (41%), alcohol (39%), and hepatitis B virus infection (22%) the commonest etiologies present. Age‐standardized HCC incidence (per 100,000, Australian Standard Population) was 10.3 (95% confidence interval [CI]: 9.0‐11.7) for males and 2.3 (95% CI: 1.8 to 3.0) for females. The VCR reported significantly lower rates of HCC: 5.3 (95% CI: 4.4 to 6.4) and 1.0 (95% CI: 0.7 to 1.5) per 100,000 males and females respectively (P < 0.0001). Conclusions: HCC incidence in Melbourne is 2‐fold higher than reported by cancer registry data owing to under‐reporting of clinical diagnoses. Adoption of current diagnostic criteria and additional capture sources will improve registry completeness. Chronic viral hepatitis and alcohol remain leading causes of cirrhosis and HCC. (Hepatology 2016;63:1205–1212)